1. Field of the Invention
This invention concerns pharmaceutical delivery forms, more particularly tablets for oral administration that disintegrate in an aqueous solution, such as saliva. The tablets disintegrate rapidly in the saliva of a subject's mouth, and can be swallowed easily without drinking water.
2. General Description of the Background
Lyophilization (which is also known as freeze-drying) is a technique for removing moisture from a wet material by freezing it and subsequently subliming moisture from it under reduced pressure. In this process, a suspension, solution or wet solid is frozen, and ice crystals in the frozen product are removed through a sublimation process at a reduced temperature and pressure that transforms ice directly into a vapor. The resulting freeze-dried product is a porous mass about the same size and shape as the original frozen mass. It has good stability, convenient reconstitutability when placed in solvent (usually water), and maintains flavor and texture similar to the original material.
Typical freeze-drying operations require three steps: freezing, removal of unbound liquid (primary drying) by sublimation from a solid directly into a vapor, and desorption of bound solvent (secondary drying) from a liquid into a vapor. Materials to be freeze-dried may be complex mixtures of solvent(s) and other substances that are cooled to form ice crystals. With further cooling, the mass becomes more rigid as the result of formation of eutectics. When the entire mass is solidified, all unbound solvent has been transformed into ice. Bound solvent, however, remains fixed as a liquid within the internal structure of the material and is not frozen.
During the sublimation phase of freeze-drying, the frozen material is exposed to a vacuum, and heat is applied to the ice crystals to sublime them. The temperature and pressure of the lyophilization process is carefully controlled such that the frozen mass is maintained below the eutectic temperature at which the mass begins to melt. Maintaining the temperature of the treated mass lower than its eutectic temperature is considered critical to providing a freeze-dried product. See, for example, U.S. Pat. No. 4,616,047 and U.S. Pat. No. 4,001,944, which stress that lyophilization occurs below the initial melting temperature of the mass. Removing unbound solvent during the primary drying step is therefore accomplished without exceeding the eutectic temperature of the composition. Direct sublimation from a solid to a vapor has been considered important to forming the microporous structure that gives freeze-dried products their porosity and reconstitutability.
Lyophilization processes have been used to prepare tablets that are described as rapidly dissolving in a subject's mouth. Such, tablets are shown in U.S. Pat. Nos. 4,371,516 and 4,946,684, as well as GB 2,111,423 and South African Patent Application No. 895546. These patents disclose pharmaceutical tablets having an open matrix network structure containing gelatin or a natural gum and a carbohydrate such as mannitol. U.S. Pat. No. 4,946,684, for example, describes tablets containing mannitol and gum that are prepared by a lyophilization process in which the tablet is initially frozen. Moisture is then sublimed from the tablet below the initial melting temperature of the mixture. Direct sublimation of liquid from the tablet has been found to produce a very porous open matrix network throughout the tablet into which saliva rapidly moves to disintegrate the lyophilized mass after it is placed in a subject's mouth.
Although the open matrix network of these lyophilized products produces a tablet that rapidly disintegrates in water or saliva, a drawback is that such tablets are very fragile, and their handling prior to placing in the mouth must be severely restricted. U.S. Pat. No. 4,305,502 attempts to overcome the problem of the freeze-dried tablet's fragility by forming and lyophilizing the tablets in the depressions of a plastic blister package. The depressions are then covered by an adherent sheet to seal the package and protect the tablets during storage.
The fragile nature of freeze-dried products has often impeded their more widespread use. Until now it has been thought that loss of tablet integrity was a necessary sacrifice to obtain a tablet that dissolved readily in the mouth.
Vacuum drying is an alternative method of removing liquid from a material by evaporating the liquid at a reduced pressure. Although vacuum drying is widely used in laboratory and industrial applications, it suffers from the drawback of producing explosive release of liquid from the material being dried. This explosive release disrupts the structure of the material, and has heretofore been considered unsuitable for commercial production of well formed or shaped products.
It is an object of the present invention to provide a process for producing improved rapidly disintegrating tablets that have enhanced structural integrity.
It is yet another object of the invention to provide an improved rapidly disintegrating tablet that can be dislodged from a blister pack with minimal damage to the tablet.
It is yet another object of the invention to provide such an improved tablet that has a taste and texture acceptable to consumers.
These and other objects of the invention will be understood more clearly by reference to the following detailed description and drawings.